Humansareunusuallysusceptibletogallstones, whichrepresentprecipitatedbileconstituentsthataccumulateinthegallbladderorelsewhereinthebiliarytree.GallstonesarecomposedpredominantlyofcholesterolorCa++ bilirubinate(cholesterolvs.pigmentstones,respectively).Theirsignificanceliesintheirpropensitytoobstructbiliaryflowandtherebyresultinpain,poortoleranceoflargefattymeals,retentionofbiliaryconstituents,and(ifleftuntreated)liverinjury.Insusceptibleindividuals,mechanismsthatnormallypreventnucleationofsaturatedbileareeitherdefectiveorovercome,andsmallcrystalsformandcangrowintogallstones.Humanbileisoftensupersaturatedintermsofitscholesterolcontent,thusincreasingtheriskforstoneformation,particularlyduringprolongedfasting.Cholesterolgallstonesareespeciallycommoninmiddle-agedwomenwhoareobese,particularlythosewhohavebornechildren.Thisincreasedprevalenceisapparentlydueatleastinparttotheabilityofestrogentoincreasehepaticcholesterolsecretion.Inseverecasesofgallstonediseasethegallbladdermayberemovedsurgically,whichisusuallyaccomplishedlaparoscopically.SmallgallstonesthathavelodgedinthebiliarytreecansometimesberetrievedendoscopicallybyinsertingasmallsnarethroughthesphincterofOddifromanendoscope.
Bile is secreted from the gallbladder in response to signals that simultaneously relax the sphincter of Oddi and contract the smooth muscle that encircles the gallbladder epithelium (
Fig. 32.12 ). A critical mediator of this response is cholecystokinin. In addition, intrinsic neural reflexes and vagal pathways, some of which themselves are stimulated by the ability of cholecystokinin to bind to vagal afferents, also contribute to gallbladder contractility. The net result is ejection of a concentrated bolus of bile into the duodenal lumen, where the constituent mixed micelles can aid in lipid uptake. Then, when no longer needed, the bile acids are reclaimed and reenter the enterohepatic circulation to begin the cycle again. However, the other components of bile are largely lost in stool, thus providing for their excretion from the body.
Bilirubin Formation and Excretion by the Liver
The liver is also important for excretion of bilirubin, which is a metabolite of heme that is potentially toxic to the body. Bilirubin is an antioxidant and also serves as a way to eliminate the excess heme released from the hemoglobin of senescent red blood cells. Indeed, red blood cells account for 80% of bilirubin production, with the remainder coming from additional heme-containing proteins in other tissues such as skeletal muscle and the liver. Bilirubin can cross the blood-brain barrier and, if present in excessive levels, results •Fig. 32.12 Neurohumoralcontrolofgallbladdercontractionandbiliarysecretion.ThepathwayalsoinvolvesrelaxationofthesphincterofOdditopermitoutflowofbileintotheduodenum.ACh,acetylcholine;CCK,cholecystokinin;NO,nitricoxide;VIP,vasoactiveintestinalpolypeptide.
in brain dysfunction secondary to neuronal cell death and the activation of astrocytes and microglia; it can be fatal if left untreated. Bilirubin and its metabolites are also notable for the fact that they provide color to bile, feces, and to a lesser extent urine. By the same token, when bilirubin accumulates in the circulation as a result of liver disease, it is responsible for the common symptom of jaundice, or yellowing of the skin and conjunctiva.